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Human gonadotropin-releasing hormone-II regulation in ovarian cancer : mechanisms and potential functional role

University of British Columbia

It is increasingly apparent that GnRH-II acts as an autocrine/paracrine regulator in non-pituitary tissues, in addition to its role in the regulation of gonadotropin synthesis, and is an important player in cancer cell biology. High levels of GnRH-II and GnRHR in malignant ovarian tumors as compared with benign ovarian tissues underlies the importance of understanding GnRH-II function in ovarian cancer. In an attempt to define the regulation of GnRH-II in these tissues, we found that a cyclic-AMP responsive element (CRE) is critical for GnRH-II promoter transcription. In this scenario, the transcription factors p-CREB, C/EBPβ and CBP are recruited to this region in a temporarily-defined manner in response to cAMP/PKA signaling, thereby enhancing GnRH-II transcription and increasing GnRH-II mRNA levels in cancer cells of reproductive tissues. We also verified that EGF/EGFR-activated p-CREB/C/EBPβ interactions target the CRE region within GnRH-II promoter to enhance GnRH-II production in ovarian cancer. Importantly, EGF-stimulated GnRH-II expression constitutes a specific autocrine loop that contributes to ovarian cancer motility. In an attempt to define the downstream mechanisms responsible for this autocrine action of GnRH-II, we identified that MMP-2 and MT1-MMP are critical mediators of GnRH-II-enhanced ovarian cancer cell invasion. Specifically, GnRH-II acts via GnRHR to up-regulate 37kDa laminin receptor precusor expression which dimerizes to yield the non-integrin 67kDa laminin receptor (67LR). This leads to an increase interaction between 67LR and laminin in the extracellular matrix, and increases MMP-2 production in ovarian cancer cells. In parellel, GnRH-II/GnRHR-activated PI3K/Akt/β-catenin signaling to up-regulate MT1-MMP production which is known to be an activator for MMP-2 zymogen. Lastly, we attempted to define the implication of 67LR in high grade serous ovarian carcinoma due to its critical role in enhancing ovarian cancer progression in our in vitro model. However 67LR did not correlate with the overall survival of stage III & IV high-grade serous ovarian cancer patients. Overall, this study contributes to our understanding of the impact of GnRH-II/GnRHR in ovarian cancer invasive potential and provides insights into the progression of ovarian cancer and the development of new therapeutic strategies.

Text

2010-11-18

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/30021

Reproductive and Developmental Sciences

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/